Alpha-(2-phenylbenzothiazol-5-yl)propionic acid

ABSTRACT

The invention concerns Alpha -methyl-2-phenyl-5-benzothiazolyl acetic acid and its acid addition salts and basic addition salts. The acetic acid compound has the following structural formula:   This new compound and its salts have a markedly lower toxicity and comparatively higher anti-inflammatory and analgesic activity compared with those of the previously disclosed 2-substituted-5 or 6-benzothiazolyl acetic acid compounds.

United States Patent [191 Wada et al.

[ ALPHA-(Z-PHENYLBENZOTHIAZOL-S- YL)PROPIONIC ACID [75] Inventors: Jin Wada, Koshigaya; Tadayuki Suzuki, Soka; Hiroki Miyamatsu, Chofu; Shinji Ueno, Tokyo; Mitsuhiro Shimizu, Chiba, all of Japan [73] Assignee: Tokyo Tanabe Company, Ltd.,

Japan [22] Filed: Aug. 16, 1973 [21] App]. N0.: 388,781

[30] Foreign Application Priority Data OTHER PUBLICATIONS Elderfield (ed.), Heterocyclic Compounds, Vol. 5, pp.

[ July 15, 1975 506-508, (N.Y.C., John Wiley & Sons, 1957).

Wagner et al., Synthetic Organic Chemistry, NY. John Wiley & Sons, 1953, pp. 411-415, 426-429.

Primary Examiner-Richard J. Gallagher Attorney, Agent, or Firm-McGlew and Tuttle [5 7] ABSTRACT The invention concerns a-methyl-Z-phenyl-S- benzothiazolyl acetic acid and its acid addition salts and basic addition salts. The acetic acid compound has the following structural formula:

This new compound and its salts have a markedly lower toxicity and comparatively higher antiinflammatory and analgesic activity compared with those of the previously disclosed 2-substituted-5 or 6- benzothiazolyl acetic acid compounds.

1 Claim, No Drawings ALPHA-(2-PI-IENYLBENZOTHIAZOL-5- YL )PROPIONIC ACID THE BACKGROUND oF THE INVENTION Gail) The new compound of the present invention has useful pharmacological properties, possessing good antiinflammatory activity and analgesic.

2. Prior Art Many medicaments have hitherto been known as having analgesic and anti-inflammatory activities. We have studied the chemical structures of some of these medicaments which are currently regarded as having good pharmacological properties and clinical results, and have supposed inductively therefrom that the benzothiazolyl acetic acid series of compounds which have previously not been synthesized should be more effective. Thus, several compounds of said series have been chemically synthesized and submitted to pharmacological and clinical tests, whereby 2-substituted-5 or 6- benzothiazolyl acetic acid compounds have been shown to be the most effective. Patent applications have already been filed concerning the above novel compounds and the synthesizing processes of the same (cf. Chemical Abstracts, 77, l9634w, German Offenlegungschrifts 2,145,178 and 2,238,761).

THE OBJECTS OF THE INVENTION One of the objects of the present invention is a derivative of said Lsubstituted-S-benzothiazolyl acetic acid having a markedly lower toxicity than those of the original benzothiazolyl acetic acid compounds. That is, a-methyl-Z-phenyl--benzothiazolyl acetic acid having the structural formula in which a methyl group is substituted for one of the hydrogen atoms in the methylene radical, of the acetic acid group contained in the original benzothiazole compound, and which has previously never been synthesized, is found to exhibit markedly lower toxicity. Another object of the invention is to provide a compound with comparatively higher pharmacological activity owing presumably to improvement of the affinity of this compound with the organic tissues of the body and of the excretion of the compound out of the living body.

SUMMARY OF THE INVENTION a-Methyl-Z-phenyl-S-benzothiazolyl acetic acid (I) a new compound with markedly towered toxity and improved pharmocological properties, may be, for example, synthesized by, (1 hydrolysis of a-methyl-2- CHCO H phenyl-S-benzothiazolyl acetonitrile; (2) decarboxylation of oz-methyl-2-phenyL5-benzothiazolyl malonic acid; or (3) a ring-closing reaction of the undermentioned amide-imidol typetautorner compounds.

These synthesizing processes for the compound (I) of the invention are further explained as follows: i i

l. Hydrolysis of a-methyl-Z-phenyl-S-benzothiazolyl acetonitrile having the structural formula:

The hydrolysis of the compound (Il) may be accomplished in solvent containing mineral acid or alkaline substance at room temperature or at higher temperatures, to give the desired compound of the invention, As the mineral acid in the above, hydrochloric acid, sulfuric acid, phosphoric acid and the like, may be employed. And sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, ammonia and the like, may be used as said alkaline substance.

The solvent used in the hydrolysis may be water or a mixed solution of water with organic solvent such as lower alkyl alcohol having l-4 carbon atom(s), dioxane, tetrahydrofuran, acetone, Z-methoxymethanol, 2-ethoxyethanol or diinethylformamide.

a-Methyl-Z-phenyl-S-benzothiazolyl acetonitrile (ll), whose melting point is l08l09C, may be prepared, for example, by introducing a methyl group into 2-phenyl-S-benzothiazolyl acetonitrile with methyl iodide, said 2-phenyl-5-benzothiazolyl acetonitrile having been synthesized by reacting 2-phenyl-5- chloromethyl benzothiazole with potassium cyanide. The above 2-phenyl-5-chloromethyl benzothiazolemay be synthesized through chlorination of 2-phenyl-5- hydroxymethyl benzothiazole which is prepared by esterification and subsequent reduction of 2-phenyl-5- benzothiazolyl carboxylic acid. I v

2. Decarboxylation of a-methyl-2-phenyl-5- benzothiazolyl malonic acid having the'structural formula: i

The decarboxylation of the compound (III) may be accomplished by either heating of the compound at l-200C or agitation of aqueous alcoholic alkaline solution of the compound at room temperature or at higher temperatures to give the desired compound of the invention. As the'alcohol in the above aqueous alcoholic alkaline solution, a lower alkyl alcohol having 1-4 carbon atom(s) may advantageously be used.

wMethyl-Z-phenyl-S-benzothiazolyl malonic acid which is the starting material in the above process, is prepared by hydrolysis of a-methyl-Z-phenyl-S- benzothiazolyl malonic acid lower alkyl ester with sodium hydroxide or potassium hydroxide in an aqueous alcoholic solution followed by acidification of the thusresulting solution with either mineral or organic acid. The above a-methyl-Z-phenyl-S-benzothiazolyl malonic acid lower alkyl ester may be synthesized by methylation of 2-phenyl-S-benzothiazolyl malonic acid lower alkyl ester with methyl iodide or dimethyl sulfate in methanolor ethanol in the presence of metallic sodium or sodium' alcolate. For example, 2-phenyl-5- benzothiazolyl malonic acid diethyl ester having the melting point Of 2- is yn iz y reaction of reaction of benzoyl chloride thereon. Thus prepared Z-phenyl-S-benzothiazolyl acetic acid ethyl ester with salt'form compounds may be converted into the acidethyl carbonate in sodium ethoxide. 7 form compounds, the melting point of which is 3. A ring-closing reaction of the amide-imidol type l58l59C, through treating the same with mineral tautomer compounds having the structural formula: acid.

where M is a hydrogen or alkali metal atom. The salts of a-methyl-2-phenyl-5-benzothiazolyl The amide type compounds (1V) in the above strucacetic acid of the present invention represent an additural formula are a-methyl-4-benzoylthio-3- tional aspect of the invention. These salts can readily benzoylaminophenyl acetic acid or salts thereof, while be obtained by reaction of basic compounds on the the imidol type compounds (V) are a-methyl-4 present benzothiazolyl acetic acid compound under benzoylthio-3-(a-hydroxybenzylidene)iminophenyl mild conditions. That is, there may be obtained, for exacetic acid or salts thereof. It can be recognized that ample, salts of alkali metal such as sodium or potasthose compounds referred to are amide-imidol type sium, aluminum salt and salts of alkaline earth metal tautomers through infra-red spectrophotometric analysuch as calcium. Similarly, salts of organic amine such sis of the compound (cf. Donald J. Cram & George S. as diethylamine .or triethanolamine may be obtained.

Hammond: ORGANIC CHEMlSTRY, pp. 182-184, Further, the present benzothiazolyl acetic acid compublished by McGraw-Hill Book Co. lnc., 1959; New pound may be converted into acid-addition salts with York, Tronto, London). An example of the alkali metal inorganic acid such as hydrochloric acid, sulfuric acid in the above tautomer compounds (IV I V) is sodium and'the like, or salts with organic acid such as citric. or potassium. acid, lactic acid and the like.

The ring-closing reaction of the above tautomer com- The new compound of the present invention has pounds may be carried out in the following manners: higher analgesic and anti-inflammatory activity, while a. Heating the of tautomer compounds of acid-form showing markedly lower toxicity. Thus, according to a without any solvent: Such heating is generally carried further feature of the invention we provide pharmaceuout in the presence of an inactive gas and/or with intical compositions comprising at least one compound creased pressure at a temperature above the melting as defined above in admixture with a physiologically point of the reactant. compatable carrier or excipient.

Heating the tautomer compounqs the of acid'form 40 The following Tables 1-3 illustrate results of toxicoin an organic solvent: As said organic solvent, the follogical or pharmacological tests of the compound lowing "f Preferably be employed: dlmethylfonl cording to the invention; Table 1 shows the acute toxicamide, dimethylsulfoxlde or mixture of each of the said ity using mice (50 Lethal Dose) Table 2 ShOWS the two solvents with another organic solvent selected from ahti ihflammatory activity assessed inhibition of lower alkyl alcohol having l 4 carbon atom), C110)" edema formation in the rat hind-paw induced by carratetrahydrofuran, acetone z'methoxyethanol and geenin injection, and Table 3 relates to an analgesic acz-ethoxyethanol' tivity test against pain induced by applying the acetic Heating tautomer Compounds of mild or Salt acid-stretching method to mice Explaining the testing form in acidlc medlum: Favorable examples of the procedures further, the acute toxicity was assesses by acidic medium in the above are organic or inorganic the Litehfie1d Wi1eoXOh method (eh pharmaeo]. acid, or a mixture of said acid with water or with or- Exp Therapq 96(1949), 99) from the data obtained ganlc Solvem- AS the acid inorganic acid Such as 72 hours after the oral or intraperitoneal administradrochloric acid, sulfuric acid, phosphoric acid or polytion of the compound to ICR mice of ten/group, each phosphoric acid, or organic acid such as acetic acid, mouse weighing 15 20 g. The ahthinflammatory monochloroacetic acid, trichloroacetic acid or tolueneity was assessed by the Winter method (eh proe See sulfomc acid, may be employed. Further, as the organic Exp Biol Med 1 l 1( 1962) 544) that is from the data S01v6! in the above, the following may advantageously obtained 3 hours after the subplantar injection of 0.05 be employed: aqueous lower alkyl alcohol havmg 1 4 ml. of l carrageenin solution to male Wister strain carbon atom(s), aqueous 2-methoxyethanol, aqueous rats of five/group each weighing g The Lethoxyethanol, dioxanei aqueous dioxane, y- 0 injection of the carrageenin solution had been adminisdrofufan, aqueous tetrahydrofuran, acetone or q tered an hour after the oral administration of the com- OU acetonepound to be tested to said rats at the rate of 100 mg./l

When the a tomer COmPOUHdS 2 of the saltkg of animal weight. Further, the analgesic activity was form are Used as ra t r al n the above P C t measured with a pain-inhibition rate assessed by the is necessary to treat these reactants with a strongly ,5 Koster method (cf. Fer. Proc. 18(1959), 412), that is acidic mediumaThe tautomer compounds (1V 2 V) of on the basis of the data obtained in the procedures of the salt form in the above process are prepared for exintraperitoneal injection of 0.6 acetic acid solution ample, by reaction of sodium sulfide on a-methyl-4- to male ICR mice of ten/group, each mouse weighing halogeno-S-nitrophenyl acetic acid followed by further about 20 g., at the rate of 0.6 mg. of acetic acid per 10 g. of animal weight, as well as the oral administration of the compound to said mice at the rate of 100 mg. per 1 kg of animal weight.

In all of the tests, phenylbutazone, which is the most current medicament, and 2-phenyl-S-benzothiazolyl acetic acid, which had been previously disclosed by us, were employed as control compounds.

Table 1 Compound tested LD 2800 p.o. compound of the invention 1650 i.p. 2-phenyl-5-benzothiazolyl 1365 p.o. acetic acid 800 i.p.

630 p.o. phenylbutazone 372 i.p.

Table 2 Antidnflammatory activity Compound tested (Inhibition rate) compound of the invention 52.0 2-phenyl-5benzothiazolyl acetic acid 46.7 phenylbutazone 45.3

Table 3 Analgesic activity Compound tested (lnhibition rate compound of the invention 71.2 71. 2phenyl-5-benzothiazolyl acetic acid 64.2 phenylhutazone 63.6 7(- SPEClFlC EMBODIMENTS The following examples serve to illustrate the invention without limiting it any way:

EXAMPLE 1 EXAMPLE 2 Sodium ethoxide solution is prepared by adding 1.1 g. (0.0478 mole) of metallic sodium to 52 ml. of absolute ethanol, and to this solution are added 17.2 g. (0.0465 mole) of 2-phenyl-5-benzothiazolyl malonic acid diethyl ester and further are added 10 ml. of methyl iodide while stirring. The resultant liquid mixture is heated under reflux for three hours, and thereafter the reacted solution is concentrated under reduced pressure to remove ethanol. The residue is extracted with ether, and the ether layer is washed with water, then with aqueous sodium hydrogensulfite solution and with water again. After being dried with sodium sulfate, the ether layer is concentrated under reduced pressure to remove ether, whereby a oily substance is obtained.

To the oily substance are added a mixed solution of 60 ml. of 14 aqueous sodium hydroxide with 60 ml. of ethanol while stirring, and the resulting liquid is heated under reflux for an hour. Ethanol is distilled out of the above reacted solution under reduced pressure and the resulting aqueous alkaline solution is cooled. After the solution is washed with ether, 2N- hydrochloric acid is added thereto while stirring and cooling, so as to crystallize out a-methyl-Z-phenyl-S- benzothiazolyl acetic acid. The formed crude crystals are recrystallized from a mixture of chloroform and ligroin, the melting point of the refined crystals being l423C. The yield is 9.4 g., corresponding to 71.8 of the theoretical amount.

The elementary analysis for C ,,H NO S:

Calcd: C, 67.82; H, 4.62; N, 4.94.

Found: C, 67.77; H, 4.58; N, 4.98.

EXAMPLE 3 2.0 g. (0.00494 mole) of acid-form compounds of the amide-imidol type tautomers (IV 2 V) are dissolved in the mixture of 50 ml. of concentrated hydrochloric acid with 15 ml. of dioxane, and the resultant solution is heated under reflux for six hours. The reacted solution is poured into ice-water to crystallize out the a-methyl-2-phenyl-5-benzothiazolyl acetic acid. The crude crystals thus obtained are washed with hot water, and recrystallized from the mixture solution of chloroform with ligroin, the melting point of the refined product being 142-3C. The yield is 1.01 g., which correspond to 72.0 of the theoretical amount.

The elementary analysis for C, H, NO S:

Calcd: C, 67.83; H, 4.63; N, 4.94.

Found: C, 67.82; H, 4.73; N, 4.90.

EXAMPLE 4 2.0 g. (0.00468 mole) of sodium salt-form compounds of the tautomers (IV 2 V) are dissolved in a mixed solution of 60 ml. of concentrated hydrochloric acid with 15 ml. of dioxane. The resultant solution is heated under reflux for six hours. The reacted solution is poured into ice-water to crystallize out a-methyl-Z- phenyl-S-benzothiazolyl acetic acid. The crude crystals obtained in the above are washed with hot water, and recrystallized from the mixed solution of chloroform with ligroin, the melting point of the recrystallized product being 142-3C. The yield is 0.99 g. which corresponds to of the theoretical amount.

The elementary analysis for C H NO sz Calcd: C, 67.83; H, 4.63; N, 4.94.

Found: C, 67.77; H, 4.50; N, 4.89.

What we claim is:

1. a-Methyl-Z-phenyl-S-benzothiazolyl acetic acid represented by the structural formula: 

1. A METHYL-2-PHENYL-5-BENZOTHIAZOLYL ACETIC ACID REPRESENTED BY THE STRUCTURAL FORMULA: 